Ray of Gout on the Horizon

29. July 2010

Gout is a metabolic disorder widely spread. Surprisingly enough - but in text books it leads a shadowy existence. For 40 years nobody developed a new remedy against gout. But a new assessment of proven therapies breathes new life into gout therapy.

Many myths have grown up and around prophylaxis and therapy. Low purine diets are supposed to help preventing it. But purine is not identical to purine. Purine of animal origin increases the uric acid level. Vegetable proteins act neutral and those originating from dairy products even lower the level a bit. Thus is does not make any sense to foreswear coffee and tea. On the other hand, a person suffering from gout should avoid excessive barbequing. Numerous gout-advancing factors join here: Pork, beer and headache pills the day after. Beer is proven to increase the uric acid level considerably more than wine. And the gout patient has to forego acetylsalicylic acid completely. This analgesic inhibits the degradation of uric acid and thus causes the gout attack.

Gout patients are often night shift patients

Quite frequently, an acute gout attack sneaks up at night, even the blanket becomes unbearable. And almost always – at least during the first attack – the big toe joint is affected. This unbearable pain is caused by an immunological reaction and a leukocyte migration with phagocytosis. Tophi are local, mostly pain-free depositions of sodium urate crystals, found in joints, sinews and cartilage deforming those.

Fast, party and fruit

The gout patient with overweight carries around another risk factor. But be warned of crash diets! Hunger during making a diet takes the patient into an acidotic metabolism situation. This changed pH level reduces the degradation of uric acid. Please warn your patients about diet drinks containing fructose: Fructose, sometimes declared as HFCS (hygh-fructose-corn-syrup) as well, is rebuilt into ADP, degrading to purine and uric acid. The study group, Choy et al. proved that such a sweet drink increases the risk for gout by 45%.

Inhibiting or promoting?

Although gout is one of the most spread diseases, a medical guideline does not exist in Germany. By inhibiting the re-absorption of uric acid in the kidneys, uricosuric drugs like Benzbromaron and Probenecid promote an increased excretion of this substance. Whenever a patient does not get along with uricostatic drugs, Benzbromaron is the second choice. The uricostatic drug Allopurinol inhibits the generation of uric acid. But during an acute attack uricostatics are a ‘no-no’. They might intensify a gout attack since uric acid crystallizes out due to the concentration gradient between serum and tissue.

Close

For 40 years, Allopurinol is the only uricostatic drug. It is effective but sometime very poorly tolerated. Those therapy losers described in literature are rather therapy objectors. In cases of overdosing Allopurinol, diseases like a life-threatening agranulocytosis impend, skin reactions like pruritus or skin rashes occur very often. Not only “Dr. House” fanatics know the Lyell-syndrome and necrotic vasculitis but also patients taking Allopurinol. The risk of skin reactions increases remarkably when a kidney insufficiency accompanies the disease, but also further drugs like calcium antagonists and NSAR raise the risk. In 2009, the committee for drugs and medication of the German medical profession warns in the “Deutsches Ärzteblatt” (German professional magazine for physicians): “Allopurinol is the major cause for Stevens-Johnson-Syndrome and toxic epidermal necrolysis in Europe and Israel.”

The erythema exsudativum multiforme (EEM) is a temporary, mostly harmless skin reaction effecting only single keratinocytes. The Stevens-Johnson-Syndrome (SJS) is a severe form of EEM. Up to 10 percent of the skin might come off. The death rate is up to five percent.The toxic epidermal necrolysis (TEN resp. former Lyell-Syndrome) can cause up to 30 percent of the skin to come off. And up to as much as 30 percent of the patients do not survive that. The rare, but under certain circumstances life-threatening dermal reactions to drugs make the searching and finding new pharmaceuticals extremely significant.

Febuxostat is “skin-friendly”

In 2010 the first non-purine-related uricostatic drug Febuxostat was admitted. This pharmacon inhibits the reduced as well as the oxidized form of the enzyme xanthinoxidase which converts hypoxanthine to xanthine and that again to uric acid. It is a significant advantage: Febuxostat does not cause any threatening skin reactions.

The APEX-study (The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat) showed: 80 mg Febuxostat is capable to decrease the serum urate concentration below 6.0 mg/dl in more patients than 300 mg of Allopurinol (65% vs. 23 %). And the follow-up study FACT (Febuxostat Versus Allopurinol Control Trial in Subjects With Gout) proved that the size of tophi shrank by about 50% under medication with Febuxostat over a period of one year. If the uric acid level was between 4 and 5 mg/dl, the urate depositions shrank even more with 84%.

The FOCUS-study showed that patients with a stable maintenance treatment (Febuxostat 40 mg, 80 mg or 120 mg) displayed an almost complete stop of gout attacks which is connected to a permanent reduction of their serum uric acid concentration. This acronym stands for “Febuxostat Open-label Clinical trial of Urate-lowering“.

Comparing the standard Allopurinol to the newcomer Febuxostat shows additional advantages: The dose does not have to be reduced in cases of kidney insufficiency and it hardly causes any drug interactions. Lots of light and little shadow. Both pharmaceuticals cause about the same number of liver disorders. The Febuxostat group displayed a slightly higher number of cardiac complications but the results could not be causally attributed to the new drug against gout. But still, the treatment with Febuxostat is not recommended for patients with a diagnosed KHK or decompensated cardiac insufficiency. Since Allopurinol is available as a generic for quite a while, the costs of treatment are comparatively low. So who’s the patient this safe but expensive gout drug makes sense for? In cases of limited kidney insufficiency and/or polymedication bringing along the risk of interaction, especially diuretics, calcium-antagonists and AT1 inhibitors. And Febuxostat is a must for patients suffering from severe skin reaction during treatment with Allopurinol.

Progress comes at a price. This will also apply to further innovations waiting down the pipeline of research. Let it be recombinant uricase pegloticase, the implantable gene-network UREX or the research of established pharmaceuticals such as Anakinra, Losartan and Fenofibrat – their “side-effect” being a reduction of the uric acid concentration. Until the day they will be admitted you might as well drink a cup of coffee containing purine.